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Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III
David R Emlet1, Puja Gupta, Marina Holgado-Madruga
1Authors' Affiliations: Brain Tumor Research Laboratories, Program in Cancer Biology, Stanford University Medical Center, Stanford; Department of Pathology, Stanford University Medical Center, Stanford; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford; Department of Neurosurgery, Stanford University School of Medicine, Stanford; Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Department of Physiology and Pharmacology, Institute for Biomedical Research, School of Medicine, University of Salamanca, Salamanca, Spain; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; and Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, Henan, People's Republic of China.
Abstract:
The relationship between mutated proteins and the cancer stem-cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGF receptor (EGFR) variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here, we show that EGFRvIII is highly coexpressed with CD133 and that EGFRvIII(+)/CD133(+) defines the population of cancer stem cells (CSC) with the highest degree of self-renewal and tumor-initiating ability. EGFRvIII(+) cells are associated with other stem/progenitor markers, whereas markers of differentiation are found in EGFRvIII(-) cells. EGFRvIII expression is lost in standard cell culture, but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII(+)/CD133(+) coexpression, self-renewal, and tumor initiating abilities. Elimination of the EGFRvIII(+)/CD133(+) population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC-specific expression and be used to specifically target this population.
Insights
A mutated protein, EGFRvIII, specifically marks cancer stem cells (CSCs) in glioblastoma. Targeting this EGFRvIII and CD133 co-expressing population effectively reduces tumor formation.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Molecular Oncology
Background:
- The role of mutated proteins in cancer stem cells (CSCs) remains poorly understood.
- Glioblastoma frequently exhibits the EGFRvIII mutation, but its expression is limited.
- EGFRvIII is an epidermal growth factor receptor (EGFR) variant resulting from gene rearrangement.
Purpose of the Study:
- To investigate the coexpression of EGFRvIII and CD133 in glioblastoma.
- To identify the specific cancer stem cell population defined by EGFRvIII expression.
- To evaluate the potential of targeting EGFRvIII-expressing CSCs for glioblastoma treatment.
Main Methods:
- Analysis of EGFRvIII and CD133 coexpression in glioblastoma cells.
- Utilizing tumor sphere culture to maintain CSC characteristics.
- Employing a bispecific antibody to target the EGFRvIII(+)/CD133(+) population.
- Assessing self-renewal and tumor-initiating capacity of CSCs.
Main Results:
- EGFRvIII is highly coexpressed with CD133, defining a potent cancer stem cell population (EGFRvIII(+)/CD133(+)).
- This CSC population exhibits enhanced self-renewal and tumor-initiating abilities.
- EGFRvIII expression is maintained in tumor sphere culture, unlike standard cell culture.
- A bispecific antibody targeting both EGFRvIII and CD133 significantly reduced tumorogenicity compared to single-epitope targeting.
Conclusions:
- Mutated oncogenes like EGFRvIII can exhibit cancer stem cell-specific expression.
- The EGFRvIII(+)/CD133(+) population represents a key target for glioblastoma therapy.
- Targeting this specific CSC population offers a promising strategy for reducing glioblastoma tumorigenicity.
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